Date: Feb 01, 2018 Author: Mark Sullivanlong Read Source: Fast Company (
click here to go to the source)
Back in 2015, a 40-year-old synthetic biologist named Christina Smolke, along with a small team of researchers at Stanford, made a huge discovery. They proved that a genetically engineered yeast could produce opioid molecules, the core ingredients of some of the world's most widely prescribed pain medicines.
Using yeast to produce things is as old as beer and bread, but with the complete mapping of, and increasing understanding of, the entire yeast genome--the totality of its DNA--the microbes are being used to produce more complex and valuable things, like fuels and medicines. Twenty percent of bioengineered drugs are now produced with microbials, including a great many produced with organisms other than yeast. But Smolke's mission to make opioids out of yeast is on another level of complexity, requiring many successful chemical reactions as the yeast metabolizes sugar.
Smolke has spent the last 15 years of her life editing the genetic language written on the chromosomes of yeast--silencing some genes, amplifying the effects of others and, most of all, adding completely new genetic code to direct specific cellular activity. In the end, the yeast perform a completely new metabolic process--a long sequence of chemical chain reactions that starts by feeding the yeast some sugar and ends with the creation of complex opioid molecules.
The implications of Smolke's discovery were huge. Suddenly it seemed possible to mass-produce opioids in a whole new way--in bioreactors, with yeast. It raised the possibility of disrupting a drug industry that still relies mainly on materials from the poppy plant to make vital pain medicines.
The whole thing was promising enough to propel Smolke and her team out of their safe confines at Stanford and into a new life as a startup company--Antheia, Inc. But the young company has a major challenge on its shoulders. It must prove that it can mass-produce opioid molecules faster, cheaper, and more reliably using yeast than the big drug companies can using the poppy.
Antheia must continue improving its Frankenyeast, making edits to the genetic code to drive it to produce more and more opioid molecules. To be an industry contender, Antheia must prove that the yeast can produce at commercial levels. Imagine millions or billions of yeast quietly metabolizing opioids inside hundreds of bioreactors housed in a large, secure facility.
If they succeed, Antheia may make a still more startling breakthrough later on. Smolke and her team aren't talking about merely mimicking in the lab what the poppy plant makes in the field. They want to improve upon Mother Nature's recipe for opioids to make them not just easier to produce, but less addictive and safer to use. As opioid addiction ravages America, just imagine that: less-addictive opioids.
It's not hard to find examples of firebrands like Antheia failing in their mission. But at a time in our history when drug overdose is the leading cause of death in people under 50 (most of them due to pain pills and heroin), there's more than just financial reasons to hope Antheia succeeds.
Living Drug Factories
While Antheia is training the yeast to make opioid molecules more efficiently, it's also developing the technology platform that manages the data needed to bioengineer the yeast.
That tech platform may be used to make other high-value drugs in the future, Smolke says. The main reason Smolke started building the platform around opioid production (and not some other class of drug), is because opioid compounds are very complex and hard to synthesize.
"Theoretically, we should be able to get to every other compound out there that you could point us to, because there's nothing yet that has been demonstrated that has greater complexity," she explains.
Smolke and her team believe the same data tools and approaches they developed while creating opioid-making yeast can be used to engineer yeast that produces cancer drugs, or drugs for arthritis or Alzheimer's.
Antheia's technology platform is essentially a collection of computational tools and reusable strings of genetic code. The computational tools are recipes for searching out (in a database) specific genes from the genomes of various organisms, like the genetic code of the poppy plant that was borrowed for use in Smolke's opioid-making yeast. The strings of genetic code, when stitched into the yeast's DNA, cause the organism to perform some specific function. One of these "off-the-shelf" pieces of genetic code might direct the yeast to produce a specific enzyme that embeds itself at a specific place in the cell wall at a specific time. That would be just one step in a complex process that may produce a high-value compound at the end.
Smolke and her team are indeed interested in efficiently producing opioid molecules but, in a sense, the whole process of doing so is also a means of training and developing the technology platform. The platform will be able to reuse many of the tricks, techniques, and tools it developed from making opioids when it's used to make other kinds of drugs in the future.
"[We'll] develop the base platform, and get the base platform in place to a point where it's ready to be commercialized," Smolke says. "Then, that's when we'd leverage that platform to go after these newer medicines."
"This is crazy"
Smolke's working relationship with yeast began in 2003 at Caltech, where she'd taken a job teaching bioengineering. She was 28. It was her first professorship, and her first shot at running a lab. She was becoming more and more interested in the interdisciplinary field of synthetic biology, which combines biology, chemistry, engineering, genomics, and computer science. In very simple terms, this branch of biology works to rewrite an organism's genetic code--the operating system that tells it how to grow and what to do--to make it behave in a desirable way. A synthetic biologist might, for example, copy the gene that makes a jellyfish glow and insert it into the DNA of a cat. Now Fluffy glows in the dark. (For the record, this has never been attempted. That we know of.)
Smolke started working with yeast because a lot was already known about its metabolism and physiology. Actually, yeast cells are our oldest organic factories. We've used them to make bread and alcohol for centuries. Yeast became a lot more useful during the 19th century when scientists figured out how to isolate it from other materials to produce things like baker's yeast.
The biggest breakthrough came in 1996 when the Genome Project announced it had mapped (sequenced) the full genome of yeast, which contains 12 million base pairs. The genetic information in yeast's natural DNA orders up the enzymes needed to do what the yeast cell normally does, which is metabolize sugar and create ethanol in a process called fermentation. But with an understanding of the DNA, scientists began to "edit" the genes in yeast to metabolize new things.
In 2003, scientists were just beginning to think about producing drugs and biofuels using microbes like yeast. Smolke wanted to push the science far forward.
"We say we want to build things with biology, and biology should be this amazing manufacturing platform, so one of the most important areas to be working in is medicines," Smolke says.
To do that she wanted to push the yeast to produce an extremely complex molecule. Opioids, she knew, were among the most complex, and mysterious. If the yeast could be engineered to make opioids, chances are they could produce lots of other compounds, too.
Smolke recalls encountering a lot of doubters and naysayers around that time. Colleagues were constantly telling Smolke and her graduate student (and later, business partner) Kristy Hawkins, "This is crazy. You'll never get it done."
And it was crazy.
By 2004, scientists had used recombinant DNA to create yeast that could manage a few directed chemical reactions. But encoding the yeast DNA to direct a string of more than 20 chemical reactions seemed impossible.
"Okay, this is impossible. Why is it impossible?" Smolke remembers asking. "What do we need to do from a technology development perspective to make it possible?"
Helped by earlier research on how poppies make opium, Smolke and her team had a general understanding of the chain of chemical events that need to take place within the yeast to produce the opioid molecules. Using several huge DNA databases, they looked for genes that directed similar events in other organisms. Then they borrowed some of that genetic code, using it as a basis for directing the necessary events in yeast.
But the genetic data used in other organisms' DNA isn't easily transferrable to the DNA of yeast. Each organism's DNA is written using a slightly different syntax. "If you just take the DNA from plants and stick them to yeast, the yeast will say, 'This is gibberish--I don't know what to make of this,'" Smolke says. Then the yeast fails to create the enzyme needed to catalyze the necessary chemical event. The production line comes to a halt. The chain reaction stops. No opioids.
So the genetic code has to be edited, translated into the yeast's language, so the microbe can read it and create the right enzyme to catalyze the right metabolic chemical in the cell. It's in the recoding of the foreign DNA that the real heavy lifting, and the real magic, happens.
"We take the DNA--it's a string of letters, A, D, T, C--then, we just basically recode it," Smolke says. "We'll say, 'Okay, change this T to a C.'"
Smolke and Hawkins kept asking why not, and continued to methodically overcome problems. In 2009, Smolke accepted a teaching job at Stanford, where she set up a new lab. She also added Kate Thodey and Isis Trenchard to her team--both were doing their postdoctoral work in the Stanford bioengineering department at the time.
With the help of the new human, financial, and scientific resources she found at Stanford, Smolke continued the work of coaxing yeast to complete the step-by-step metabolic process of producing opioid molecules.
Then in 2015, Smolke's "crazy" idea finally succeeded.
The yeast produced two key opioid molecules: thebaine and hydrocodone. Thebaine is one of the molecules produced by the poppy, but it has to be chemically altered to create a core ingredient for pain meds. Hydrocodone, on the other hand, is a more valuable molecule because it's a finished analgesic compound requiring no further chemical alterations. To get from thebaine to hydrocodone, Smolke and her team introduced three extra genes' worth of instructions into the yeast's DNA.
When the research was published in the journal Science on September 4, 2015, the synthetic biology world immediately knew something big had happened in the history of the nascent science.
"Their study represents a tour de force in the metabolic engineering of yeast," wrote Jens Nielsen, a chemical engineer and director of Chalmers University of Technology in Sweden, in Science in 2015. "It clearly represents a breakthrough advance for making complex natural products in a controlled and sustainable way."
From Science to Startup
Several months before the publication of the research paper in Science, when it had become clear that the Frankenyeast would produce opioid molecules, Smolke decided to take a leave from teaching at Stanford and put her energy into Antheia. Hawkins, Thodey, and Trenchard came with her. It was time for Smolke and her team to turn pro.
The company now lives in a small rented office space in Menlo Park, not too far from Stanford. It's paying rent and salaries, reassuring investors, and furiously working toward some cash-positive day in the future.
Antheia operates in part on four grants--two from the National Science Foundation (NSF) and two from National Institutes of Health (NIH). One of the NIH grants came from National Institute on Drug Abuse (NIDA). Most of Antheia's funding comes from venture capital investors. The company raised $1.97 million of seed funding in 2015. Among the first investors was Ram Shriram, who was also one of Google's first investors and a member of the search giant's original board of directors. (Shriram declined Fast Company's interview requests.) In 2017 Antheia raised an "A" round of an undisclosed amount. The new investors were also not disclosed.
All that money is riding on whether or not Antheia can prove that making opioids in yeast is more cost-efficient than doing so with materials from the poppy plant.
It's a tall order. Christina Agapakis, a synthetic biologist at Ginkgo Bioworks in Boston, points out that some other pharmaceuticals are already mass-produced by recombinant microbials like yeast. But, she says, since opioids require a long and complex metabolic process in the yeast, it may be technically harder for Antheia to scale up production to commercial levels. The company continues to tweak its genetic formulas in pursuit of that goal.
The Opportunity
If the yeast rise to the occasion, Antheia could enter the market as a provider of active pharmaceutical ingredients (APIs) to drug companies that produce branded pain medicines and generics.
It's a large and growing market, driven by the increasing need of medications for baby boomers as they age. San Francisco-based Grand View Research says the global API market will be worth 239.8 billion by 2025. Opioid compounds are just a segment of that market, but pain medications are some of the most widely prescribed.
Antheia might grab a share of the market by producing and selling opioid compounds for less than current providers do.
"There are only a few routes to synthesis," Antheia's Thodey says, and getting there through bioengineered yeast may be the hardest.
Today, the old way is still the least expensive way--that is, making opioid compounds using organic material from the poppy plant.
API companies like Mallinckrodt Pharmaceuticals and Rhodes Technologies import raw material harvested from the Papaver somniferum or "opium poppy" grown in Tasmania, Turkey, India, and Australia. The plants grow waist-high; at the top, flowers surround a golfball-sized seed pod. After the flowers fall off, cuts are made in the seed pod to let the milky "gum" substance leak out. This opium resin is then partially dried and bagged or rolled into balls for shipment. After receiving the opium material, API companies run a chemical process on it to create active ingredients like hydrocodone. The price of opioid APIs are determined by the cost of the raw opium material and the cost of the chemical processing that needs to be done.
Thodey says other people have successfully tried to synthesize opioid molecules through chemistry, but it's proven to be prohibitively expensive at a large scale.
The third route to synthesis of opioid compounds is through the use of microbials, as Antheia does with yeast. It's possible Antheia could face competition from other startups using microbials to produce high-value compounds. But Antheia may enjoy a certain amount of protection from these would-be challengers; it's hard to imagine a tougher or longer "barrier to entry" than the one Antheia has been crossing for the last decade, and that it continues to cross.
"The stuff they're doing is really hard. You need a small, focused team that really lives and dies by making it work," says Karl Handelsman, investments director at the Roche Venture Fund based at Genentech, one of Antheia's investors. "And that's what Christina has managed to put together. She has some very good people."
A like-minded competitor would have to go through a similar (expensive) process, and would presumably have to work around the patents protecting Antheia's work.
It's most likely that Antheia will be competing with companies that produce the core opioid ingredients using organic material from the poppy plant--and that method is itself not likely to get cheaper. The poppy, it turns out, is heavily regulated in the United States. Poppy plants can't be legally grown in the U.S. Nor is the importation of whole poppy plants legal; only the raw organic material harvested from the plant can be brought in. After the expense of importing the raw materials, drug companies have to pay the cost of the additional chemical processes needed to convert the raw material into active opioid compounds.
Though it's yet to be seen how expensive producing opioids at scale ends up being for Antheia, one bright spot for the startup is that its yeast method is not subject to those costs. But Antheia still has to contend with lots of other costs in the production process that it may not yet be able to perfectly predict. If the process requires more bioreactors, more yeast, more sugar, and more R&D time than expected, the then costs will naturally go up and the opioid compounds Antheia makes might not be able to be sold at a price that's low enough to undercut the incumbents.
However, Thodey thinks that once you have an understanding of the yeast and the optimal conditions for producing lots of opioid molecules, you can just maintain those factors as the numbers of yeast climb upward. The company is making hundreds of tweaks to the DNA of the yeast to cause the right enzymes to create the right metabolic actions to produce as many opioids as they may need.
Humanitarian Potential
Smolke says one result of building a more efficient way to make drugs is the opportunity to make vital medications available to parts of the world where they're currently scarce. The economics of making painkillers have led the big drug makers to focus on Western markets.
The biggest is the United States, which uses 80% of the global supply of painkillers--yet has only 5% of the world's population. In many countries, opioids are reserved for very serious injuries, which leads to a lot of suffering.
Making pain meds out of materials from the poppy plant, Smolke emphasizes, is costly and unpredictable: Growing and transporting materials from the poppy is expensive, and whole poppy crops can easily be decimated by inclement weather.
"Our supply chains and the way that we make these medicines is totally messed up," Smolke says. Antheia's yeast-based and lab-based way of making opioids might prove far cheaper and far more practical than using materials from the poppy. This in turn might dramatically improve the economics of selling pain medications in poorer parts of the world.
"We really do need better medicines, not just better medicines for us in the U.S., but better medicines that can really have an impact globally," Smolke believes.
But perhaps the most tantalizing implication of Smolke's work is the possibility of engineering the yeast to produce opioids with fewer side effects, including, potentially, addictiveness.
"That's where I really see the power and value of this technology," Smolke believes. "We can actually make what the poppy can't make," she believes, hoping that "thus we can get to these higher-value, more sophisticated medicines more cheaply."
Down the road, it may be possible to "design" and mass-produce medicines with all the pain relieving qualities of today's drugs but without the addictive properties that are killing so many people. (Opioid overdose took around 58,000 lives in the U.S. last year--more than the Vietnam War). If you can make (genetically engineer) the machine (the yeast) that makes the drug, you may be able to alter the machine to make a better, less dangerous drug.
The yeast could potentially be the engine behind a new paradigm in pain management characterized by drugs, one that evolves past the current devil's bargain people who are suffering physical discomfort have to make: choosing effective pain relief despite the high risk of addiction. It could also help bring more pain medicines to more people in the developing world; in many countries, lack of access is due in large part to government policies that severely limit access to opioid medications out of fears over their addictiveness.
It's a very hard problem. Scientists have tried many ways of removing harmful side effects (respiratory depression, constipation, nausea, addiction) from opioids, but so far it's proved unworkable. The side effects are practically intrinsic to the poppy's natural compounds--thebaine and morphine. Synthetic chemistry has largely failed to process them out, partly because of the complexity of the opioid molecules. Antheia would have to accomplish what the synthetic chemists could not by altering the metabolism of yeast.
Short of designing addiction-free pain drugs, Antheia might find a more immediate niche making nalopioid ingredients for improved pain drugs.
"They're used to make the newer formulations that are coming on to the market that are abuse-deterrent, and extended release, and basically made so that there's less likelihood for abuse and addiction," Smolke says. Given current abuse rates, nalopioids are very likely a growth market.
Nalopioids are also the key ingredient in opioid addiction therapy drugs like Suboxone, which limit the addicts' cravings for opiates. The problem is, the drugs are so expensive that most insurers won't cover them, and many addicts can't afford them.
Nalopioids are more expensive because they're harder to make than more basic compounds like morphine. "They require heavy modification of the compounds that we get from the poppy," Smolke says. Making nalopioids with yeast (instead of from poppies) could obviate the need for the expensive modifications. That means if the yeast proved to be a far less costly means of producing nalopioids, more people might get access to drugs like Suboxone.
Big Questions
It's hard to predict exactly how disruptive Antheia will be to the pharmaceutical world not only because it has yet to scale its production to commercial levels, but also because the drug industry and its prices depend on an unpredictable research and development process and on the stability of the poppy supply.
Big Question No. 1 is how fast can Antheia scale its platform up to commercial production and start selling product?
Smolke claims Antheia's goal of commercialization might be closer than some realize. "There's not a large understanding within that industry of how quickly this kind of technology can move and how quickly it's being commercialized, mainly because there just hasn't been a precedent for this."
Big Question No. 2 is whether or not Antheia will be able to sell its opioid compounds at a price low enough to undercut incumbent API providers even if poppy material prices drop?
That one's harder to answer. One prominent investor told me that while there's readily available organic compound, it's not as easy to see a viable opportunity for companies like Antheia. That's a reasonable point of view. It's not hard to find examples of startups that sought to market bio-alternative products but ultimately failed to consistently undercut the prices of incumbents' products made using traditional methods.
For its part, Antheia's eventual production costs will depend on the way its yeast-based production model grows up from one yeast to thousands of yeast in one bioreactor, and from there to billions of yeast in a whole facility full of bioreactors.
We'll know in a year or two whether or not Antheia's yeast can churn out enough molecules to challenge existing base compound providers like Mallenkrodt. A lot is riding on it. More than a decade of Christina Smolke's life, for one thing, as well as the investment money from Handelsman and others.
If Antheia proves it can sell enough opioid compounds at consistently lower prices than other suppliers, that would open the door to the platform churning out molecules for other high-value drugs--including, perhaps, less expensive nalopioids needed for the treatment of overdose and ongoing treatment of addicts. It would be a breakthrough of even larger proportion than Smolke et al's proof in 2015 that yeast could produce opioids. It might immediately increase the influence of synthetic biology in the drug industry.
Smolke believes it's a tectonic change that must come to the industry sooner or later.
"We co-opted a lot of molecules that nature happens to make to be some of our most important medicines," she says. "The fact is that most of the medicines that we need are not going to come from nature directly, because these plants are not making these compounds for medicines for humans, they're making them for their own purposes. We're going to hit this wall."
It may take the work of small, determined startups like Antheia to be the catalysts that lead the industry toward new ways of making better drugs. It also may take people with the moxie, single-minded focus, and total commitment of Smolke, who was a scientist long before she was an entrepreneur, and still acts and speaks like one.
"If we're saying we want to move to this bio-economy, we want to really take biotechnology and genetic engineering to the next level and be able to make things, let's really jump in--what are the most complex molecules we can potentially make? What's complex and valuable?"
"Then, let's figure out how to do it," Smolke says. "Let's address the technical challenges, and why people are saying you can't do it. It's impossible, let's figure out why that is, and let's make it possible.
